The ethics of conducting medical trials can be tricky. There is always the risk someone could be exposed to a drug that is dangerous, or they could miss out on something of potential benefit.
So these issues need debating in medical journals.
But doctors and medical researchers are not ethicists and this was, I think, demonstrated by an article recently in the prominent journal The New England Journal of Medicine.
So bad was an argument made by these experts, that it’s really worth thinking about for a minute.
» The issue
The debate was about whether or not it is ethical to conduct placebo controlled trials of drugs that treat osteoporosis. The trouble is that we now have very good drugs that significantly reduce the rates of fractures, and giving someone a placebo is denying them something that will do them a great deal of good.
This problem needs to be weighed against the fact that controlled trials are needed to develop newer, better drugs. So, you can see that there is an issue here that needs to be debated.
One of the central questions, is whether there are alternative ways of trialling new drugs, without using placebos. One such way is to compare new drugs to existing drugs: “head-to-head trials”.
But the practical problem with conducting head-to-head trials is that they need to be much larger in order to show statistically significant effects.
» The good argument
In one article in the journal, two doctors said that this practical concern doesn’t matter.
The challenges associated with head-to-head trials “should not be considered an ethical justification for administering placebo to some patients, which would result in potentially preventable fractures,” they said.
This seems to me to be a good argument. The underlying principle is that the alternative to a course of action being practically difficult, doesn’t make that action ethical. Just because doing head-to-head trials is difficult doesn’t mean that giving people placebos is ethically OK.
» The bad argument
But the guys arguing that placebo trials can still be ethical in osteoporosis expected this argument, and rebutted it with what I think is one of the worst ethical arguments I have come across in a medical journal.
Ultimately, any trial involving [an active] comparison group would, given its necessarily larger size, result in more fractures over the duration of the trial than would be observed in a placebo-controlled study and, thus, it would offer no ethical advantage over the latter.
It seems to me that they’re defending the principle that the primary ethical consideration is the total number of negative outcomes observed in a trial.
That’s what they’re saying, right? Read it again:
…would, given its necessarily larger size, result in more fractures over the duration of the trial than would be observed in a placebo-controlled study and, thus, it would offer no ethical advantage over the latter.
But that is an absurd principle to defend. On the basis of that principle, if we were to do a large trial where we gave patients the very best care we know of, it could be unethical because if it’s large enough, it will observe a lot of negative outcomes.
Indeed, it would be an argument against collecting data on real-world outcomes in what are known as “observational studies”. If you observe a million people, then there will be lots of negative outcomes. But that clearly doesn’t make observing them unethical.
I put this point to the lead author in an email. I received a very nice and thoughtful reply, but I don’t think any light was shed on the matter. (I’ll post the reply in the comments.)
» The relevant ethical principle
Giving a placebo to 100 people, and seeing 5 negative outcomes is worse than giving best treatment to 100,000 people and seeing a few more negative outcomes.
The relevant issue is not the number of negative outcomes, but the risk of negative outcomes being imposed on each patient. It’s about the intervention we’re making, and whether that is ethical.
So we need to make sure we’re not giving people placebos when they could benefit from an active treatment and we need to make sure that active treatments we are trialling are likely to be safe and effective. We can never be sure, but with these matters, it’s always about the risk — the probability of harm.
Stein CM, & Ray WA (2010). The ethics of placebo in studies with fracture end points in osteoporosis. The New England journal of medicine, 363 (14) PMID: 20879888
Rosen CJ, & Khosla S (2010). Placebo-controlled trials in osteoporosis–proceeding with caution. The New England journal of medicine, 363 (14) PMID: 20879887